chr14-92071010-C-CCTGCTGCTGCTG

Variant names:

• chr14-92071010-C-CCTGCTGCTGCTG
• rs193922928
• NM_004993.6:c.904_915dupCAGCAGCAGCAG

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BS1 BS2

The NM_004993.6(ATXN3):​c.904_915dupCAGCAGCAGCAG​(p.Gln302_Gln305dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0087 (24 hom., cov: 20)
  • Exomes 𝑓: 0.0053 (165 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_004993.6 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.168
• Publications: 1 publications found

Genes affected

ATXN3 (HGNC:7106): (ataxin 3) Machado-Joseph disease, also known as spinocerebellar ataxia-3, is an autosomal dominant neurologic disorder. The protein encoded by this gene contains (CAG)n repeats in the coding region, and the expansion of these repeats from the normal 12-44 to 52-86 is one cause of Machado-Joseph disease. There is a negative correlation between the age of onset and CAG repeat numbers. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2016]

ATXN3 Gene-Disease associations (from GenCC):

• Machado-Joseph disease

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Machado-Joseph disease type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Machado-Joseph disease type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Machado-Joseph disease type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000303901 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004993.6
• BP6: Variant 14-92071010-C-CCTGCTGCTGCTG is Benign according to our data. Variant chr14-92071010-C-CCTGCTGCTGCTG is described in ClinVar as Benign. ClinVar VariationId is 931861.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00866 (1234/142494) while in subpopulation AFR AF = 0.0202 (734/36306). AF 95% confidence interval is 0.019. There are 24 homozygotes in GnomAd4. There are 596 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1234 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004993.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	NM_004993.6	MANE Select	c.904_915dupCAGCAGCAGCAG	p.Gln302_Gln305dup	conservative_inframe_insertion	Exon 10 of 11	NP_004984.2
	ATXN3	NM_001127696.2		c.859_870dupCAGCAGCAGCAG	p.Gln287_Gln290dup	conservative_inframe_insertion	Exon 9 of 10	NP_001121168.1	P54252-4
	ATXN3	NM_001127697.3		c.751_762dupCAGCAGCAGCAG	p.Gln251_Gln254dup	conservative_inframe_insertion	Exon 8 of 9	NP_001121169.2	A0A0A0MS38

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	ENST00000644486.2	MANE Select	c.904_915dupCAGCAGCAGCAG	p.Gln302_Gln305dup	conservative_inframe_insertion	Exon 10 of 11	ENSP00000496695.1	P54252-2
	ATXN3	ENST00000532032.5	TSL:1	c.904_915dupCAGCAGCAGCAG	p.Gln302_Gln305dup	conservative_inframe_insertion	Exon 10 of 10	ENSP00000437157.1	P54252-1
	ATXN3	ENST00000503767.5	TSL:1	c.859_870dupCAGCAGCAGCAG	p.Gln287_Gln290dup	conservative_inframe_insertion	Exon 9 of 10	ENSP00000426697.1	P54252-4

Frequencies

GnomAD3 genomes AF: 0.00862 AC: 1227 AN: 142384 Hom.: 24 Cov.: 20

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.00227

Gnomad AMR AF: 0.00847

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00232

Gnomad FIN AF: 0.00101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00510

Gnomad OTH AF: 0.00928

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00534 AC: 7015 AN: 1314362 Hom.: 165 Cov.: 92 AF XY: 0.00515 AC XY: 3384 AN XY: 657202

African (AFR) AF: 0.0251 AC: 691 AN: 27538

American (AMR) AF: 0.00548 AC: 222 AN: 40506

Ashkenazi Jewish (ASJ) AF: 0.000123 AC: 3 AN: 24398

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37452

South Asian (SAS) AF: 0.00137 AC: 109 AN: 79478

European-Finnish (FIN) AF: 0.00215 AC: 105 AN: 48908

Middle Eastern (MID) AF: 0.00427 AC: 22 AN: 5148

European-Non Finnish (NFE) AF: 0.00556 AC: 5536 AN: 995836

Other (OTH) AF: 0.00592 AC: 326 AN: 55098

GnomAD4 genome AF: 0.00866 AC: 1234 AN: 142494 Hom.: 24 Cov.: 20 AF XY: 0.00861 AC XY: 596 AN XY: 69228

African (AFR) AF: 0.0202 AC: 734 AN: 36306

American (AMR) AF: 0.00847 AC: 122 AN: 14412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.00 AC: 0 AN: 4634

South Asian (SAS) AF: 0.00209 AC: 9 AN: 4310

European-Finnish (FIN) AF: 0.00101 AC: 10 AN: 9884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00510 AC: 339 AN: 66412

Other (OTH) AF: 0.00917 AC: 18 AN: 1962

Alfa AF: 0.00 Hom.: 345

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Azorean disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
Mutation Taster		=80/20	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs193922928; hg19: chr14-92537354; COSMIC: COSV100515695; COSMIC: COSV100515695;